Product comprising a transduction inhibitor of heterotrimeric G protein signals combined with another anti-cancer agent for therapeutic use in the treatment of cancer

1 . A composition for treating cancer comprising an anti-tumorally effective amount of a product comprising at least one transduction inhibitor of heterotrimeric G protein signals and at least one other anti-cancer agent selected from the group consisting of prenyltransferase inhibitors, taxol and its analogues, gemcitabine and camptothecin and its analogues, administered simultaneously, separately or spread over a period of time and a pharmaceutical carrier.

2 . The composition of claim 1 wherein the other anti-cancer agent is a prenyltransferase inhibitor.

3 . The composition of claim 2 wherein the prenyltransferase inhibitor is a farnesyltransferase inhibitor.

4 . The composition of claim 1 comprising at least one transduction inhibitor of heterotrimeric G protein signals of the formula

corresponding to the sub-formulae

wherein X is R 12 and Y is R 8 , or X and Y together complete a ring with 6 members, the X—Y mnixture is —CH(R 8 )—CH(R 9 )— radical;

R 1 is selected from the group consisting of H, alkyl and alkylthio;

R 2 and R 3 are individually H or alkyl;

R 4 is H 2 or O;

R 5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl unsubstituted or substituted by a member selected from the group consisting of alkyl, —O—R 10 —S(O) m R 10 (m is 0, 1, or 2), —N(R 10 )R( 11 ), —N—C(O)—R 10 , —NH—(SO 2 )—R 10 , —CO 2 —R 10 , C(O)—N(R 10 ) (R 11 ), and —(SO 2 )—N(R 10 ) (R 11 );

R 6 and R 7 are individually selected from the group consisting of H, —C(O)—NH—CHR 13 —CO 2 R 14 , alkyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl, the latter four unsubstituted or substituted by a member selected from the group consisting of OH, alkyl, alkoxy, —N(R 10 )(R 11 ), —COOH, —CON(R 11 ) (R 11 ), and halo, or R 6 and R 7 together form aryl or heterocycle;

R 8 and R 9 are individually selected from the group consisting of H, alkyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl unsubstituted or substituted by a member of the group consisting of

—OH, alkyl, alkoxy —N(R 10 )(R 11 ), —COOH, —CONR( 10 )(R 11 ) and halo;

or R 8 and R 9 together form aryl or heterocycle;

R 10 and R 11 are individually selected from the group consisting of H, aryl, heterocyclyl, alkyl, aralkyl and heterocyclylalkyl;

R 12 is selected from the group consisting of NR 9 , S, or O;

R 13 is alkyl unsubstituted or substituted by a member selected from the group consisting of alkyl, —OR 10 , —S(O) m R 10 (m is 0, 1, or 2) and —N(R 10 ) (R 11 )

R 14 is H or alkyl;

combined with at least one other anti-cancer agent selected from the group consisting of gemcitabine, taxol, taxol analogues and farnesyltransferase inhibitor selected from the group consisting of:

a compound of the formula

wherein n1 is 0 or 1;

X, is independently, each time that it occurs, (CHR 11 ) n3 (CH 2 ) n4 Z (CH 2 ) n5 ;

Z is selected from the group consisting of O, N(R 12 ), S, and a bond;

n3 is, independently, each time that it occurs, 0 or 1;

each of n4 and n5 are, independently, each time that they occur, 0, 1, 2 or 3;

Y is, independently, each time that it occurs, selected from the group consisting of CO, CH 2 , CS, and a bond;

R 1 is selected from the group consisting of

and N(R 24 R 25 ) each of R 2 , R 11 , and R 12 are individually, each time that it occurs, selected from the group consisting of H, —(C 1-6 )alkyl and an aryl unsubstituted or substituted by at least one member selected from the group consisting of R 8 or R 30 , each substituent being chosen independently of the others;

R 3 is, independently, each time that it occurs, selected from the group consisting of H, —(C 1-6 )alkyl, —(C 2-6 )alkenyl, —(C 2-6 )alkynyl, —(C 3-6 )cycloalkyl, —(C 3-6 )cycloalkyl(C 1-6 )alkyl, —(C 5-7 )cycloalkenyl, —(C 5-7 )cycloalkenyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, heterocyclyl, and heterocyclyl(C 1-6 )alkyl unsubstituted or substituted by at least one R 30 , each substituent being chosen independently of the others;

each of R 1 and R 5 are, independently, each time that it occurs, selected from the group consisting of H, —(C 1-6 )alkyl, —(C 3-6 )cycloalkyl, aryl and heterocyclyl unsubstituted or substituted by at least one R 30 , each substituent being chosen independently of the others, or R 4 and R 5 when taken together with the carbon atoms to which they are attached together form aryl;

R 6 is, independently, each time that it occurs, selected from the group consisting of H, —(C 1-6 )alkyl, —(C 2-6 )alkenyl, —(C 3-6 )cycloalkyl, —(C 3-6 ) cycloalkyl(C 1-6 )alkyl, —(C 5-7 ) cycloalkenyl, —(C 5-7 ) cycloalkenyl(c 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, heterocyclyl and heterocyclyl(C 1-6 )alkyl unsubstituted or substituted by at least one member selected from the group consisting of —OH, —(C 1-6 )alkyl, —(C 1-6 )alkoxy, —N(R 8 R 9 ), —COOH, —CON(R 8 R 9 ) and halo, each substituent being chosen independently of the others;

R 7 is, independently, each time that it occurs, selected from the group consisting of H, ═O, ═S, H —(C 1-6 )alkyl, —(C 2-6 )alkenyl, —(C 3-6 )cycloalkyl, —(C 3-6 )cycloalkyl(C 1-6 )alkyl, —(C 5-7 ) cycloalkenyl, —(C 5-7 )cycloalkenyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, heterocyclyl and heterocyclyl(C 1-6 )alkyl unsubstituted or substituted with at least one member selected from the group consisting of —OH, —(C 1-6 )alkyl, —(C 1-6 )alkoxy, —N(R 8 R 9 ), —COOH, —CON(R 8 R 9 ) and halo, each substituent being chosen independently of the others;

each of R 8 and R 9 are, independently, each time that it occurs, selected from the group consisting of H, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, aryl, and aryl(C 1-6 )alkyl;

R 10 is C;

or, when n1=0, R 6 and R 7 can be taken together with the carbon atoms to which they are attached form aryl or cyclohexyl;

R 21 is, independently, each time that it occurs, selected from the group consisting of (C 1-6 )alkyl and aryl(C 1-6 )alkyl unsubstituted or substituted by at least one R 8 or R 30 , each substituent being chosen independently of the others;

R 22 is selected from the group consisting of H, (C 1-6 )alkylthio, (C 3-6 )cycloalkylthio, R 8 —CO—, and

each of R 24 and R 25 is independently, each time that it occurs, selected from the group consisting of H, (C 1-6 )alkyl and aryl (C 1-6 ) alkyl;

R 30 is, independently, each time that it occurs, selected from the group consisting of —(C 1-6 )alkyl, —O—R 8 , —S(O) n6 R 8 , —S(O) n7 N(R 8 R 9 ), —N(R 8 R 9 ), —CN, —NO 2 , —CO 2 R 8 , —CON(R 8 R 9 ), —NCO—R 8 , and halogen, each of n6 and n7 is, independently, each time that it occurs, 0, 1 or 2;

said heterocyclyl is selected from the group consisting of azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl-N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl and thienyl;

said aryl radical being phenyl or naphthyl;

with the proviso that when n1=1, R 10 is C and R 6 is H, then R 10 and R 7 can, taken together, form

or when n1=1, R 10 is C, and R 7 is ═O, H, or ═S, then R 10 and R 6 can, taken together, form

with each of X 1 , X 2 , and X 3 is independently selected from the group consisting of H, halogen, —NO 2 , —NCO—R 8 , —CO 2 R 8 , —CN, and —CON(R 8 R 9 ); and

when R 1 is N(R 24 R 25 ), then n3 is 1, each of n4 and n5 is 0, Z is a bond, and R 3 and R 11 can, taken together, form

n2 is an integer from 1 to 6, and each of X 4 and X 5 is independently selected from the group consisting of H, —(C 1-6 )alkyl and aryl, or X 4 and X 5 taken together, form (C 3-6 )cycloalkyl,

a compound of the formula

wherein R 1 is selected from the group consisting of H, —OR 10 and —NR 11 R 12 ;

R 2 is H or alkyl;

R 3 , R 4 and R 5 are independently selected from the group consisting of H, halogen, alkyl, trihalomethyl, hydroxy, cyano and alkoxy;

R 6 is H or alkyl;

R 7 is selected from the group consisting of halogen, alkyl, hydroxyalkyl, amino, and hydroxycarbonyl;

R 8 and R 9 are independently selected from the group consisting of H, halogen, cyano, alkyl, trihalomethyl, alkoxy, alkylthio and dialkylamino;

R 10 is selected from the group consisting of H, alkyl and alkylcarbonyl;

R 11 is H or alkyl;

R 12 is selected from the group consisting of H, alkyl and alkylcarbonyl;

and Y is O or S;

and of a pharmaceutically acceptable salt of a compound of formula (II) or a compound of formula (III).

5 . A composition of claim 4 , wherein the transduction inhibitor of heterotrimeric G protein signals is a compound of sub-formula (I A ) wherein:

R 1 is H;

R 2 and R 3 are independently H or lower alkyl;

R 4 is O;

R 5 is selected from the group consisting of H, lower alkyl, cycloalkyl and cycloalkylalkyl;

R 6 is aryl unsubstituted or substituted by a member selected from the group consisting of OH, alkyl, lower alkoxy, —N(R 10 ) (R 11 ), —COOH, —CON(R 10 ) (R 11 ) and halo;

R 10 and R 11 are independently H or lower alkyl;

and a pharmaceutically acceptable salt thereof.

6 . A composition of claim 4 wherein the anti-cancer agent combined with the transduction inhibitor of heterotrimeric G protein signals is a compound of the formula

wherein R 1 is

R 21 is aralkyl unsubstituted or substituted by at least one member selected from the group consisting of halogen, cyano, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

R 4 is aryl unsubstituted or substituted by at least one member of the group consisting of halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

X is alkylene of 1 to 6 carbon atoms;

Y is CO;

n1=1, R 10 is C, R 6 is H and R 10 and R 7 taken together, form

each of X 1 , X 2 , and X 3 is independently H or halogen and a pharmaceutically acceptable salt thereof.

7 . The composition of claim 4 wherein the anti-cancer agent combined with the transduction inhibitor of heterotrimeric G protein signals is a compound of the formula

wherein R 1 is OH or NH 2 ;

R 2 is alkyl;

one of R 3 , R 4 and R 5 is halogen;

R 6 is alkyl;

one of R 8 and R 9 is halogen;

Y is O;

and a pharmaceutically acceptable salt thereof.

8 . A composition of claim 1 wherein the inhibitor of G proteins is selected from the group consisting of

-7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; and

-7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;

and pharmaceutically acceptable salts thereof.

9 . The composition of claim 1 , wherein the anti-cancer agent is selected from the group consisting of 1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-methoxyphenyl)imidazo[1,2c][1,4]benzodiazepine,4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoroimidazo[1,2a](1,4)-benzodiazepine; (±)-4-(3-chlorophenyl)-6-[(4-chloro-phenyl)-amino-(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)quinolinone, taxol and gemcitabine.

10 . The composition of claim 1 wherein an additional anti-cancer compound, different from the anti-cancer agent combined with the transduction inhibitor of heterotrimeric G protein signals, is selected from the group consisting of

-1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-methoxyphenyl)imidazo[1,2c][1,4)benzodiazepine;

-4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl-1-oxoethyl)-1,2-dihydro-8-fluoro-imidazo[1,2a](1,4]-benzodiazepine;

-±-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-amino-(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)quinolinone;

taxol;

gemcitabine;

and a pharmaceutically acceptable salt thereof.

11 . The composition of claim 7 wherein R 2 is methyl.

12 . A method of treating cancer in warm-blooded animals comprising administering to warm-blooded animals in need thereof an antitumorally effective amount of a composition of claim 1 .

13 . A method of treating cancer in warm-blooded animals comprising administering to warm-blooded animals in need thereof an antitumorally effective amount of a composition of claim 4 .

14 . A method of treating cancer in warm-blooded animals comprising administering to warm-blooded animals in need thereof an antitumorally effective amount of a composition of claim 10.